Problems in the Bioinorganic Chemistry of Molybdenum and Tungsten

该奖项在无机、生物无机和有机金属化学项目中支持哈佛大学Richard H. Holm教授的研究，该研究集中在钼和钨的氧转移酶和羟化酶催化的转化上。其中许多反应是纯氧原子（oxo）转移过程，其中氧原子被插入或移除（氧转移酶），而其他反应则利用金属配位氢氧化物（羟化酶）进行催化反应。含钨酶通常存在于嗜热细菌和古细菌中。在几乎所有的情况下，氧原子的最终来源或汇是水。催化中心含有单核钼或钨原子，与一个或两个吡翼二硫代烯配体结合。实验方法包括合成酶催化位点的低分子量类似物及其在反应性研究中的应用。该研究建立在酶催化位点类似物的合成和反应性结果的基础上，这些酶含有两个pyranopterindithiolene配体，并通过原子转移还原有机s -氧化物和n -氧化物。天然配体由合成的二硫代烯表示，当与钼或钨结合时，其功能为烯-1,2-二硫代酸盐，并密切模拟了天然配位产生的电子环境。为了研究硒酸还原酶、亚砷酸盐氧化酶、甲酸脱氢酶、乙炔水合酶、醛氧化酶和一氧化碳脱氢酶的类似反应，提出了一种新的、可能是通用的二硫代配合物的合成方法。其他系统包括转羟基化酶和乙苯脱氢酶。功能模拟系统将底物转化为酶（但不一定在相同的反应速率域中），其金属位点与酶的金属位点可信地相似，并提供接近酶位点几何和电子结构的方法，是本研究的重点。钼和钨酶与处理碳、氮、硫、砷和硒的全球循环有关。某些酶，如亚硫酸盐氧化酶和黄嘌呤氧化酶，存在于人体内；它们的故障会导致严重的健康风险。例如，亚硫酸盐氧化酶的缺乏会导致智力迟钝。生物合成吡喃蝶二硫代烯配体的能力降低将导致所有钼酶缺乏，并伴有包括神经系统综合征在内的疾病。拟议研究的更广泛的潜在影响来自于对生物钼/钨中心的结构、功能和机制的更好理解，并将这些信息整合到改进的地球化学和环境循环的解释中，这些元素和酶底物中所含的元素。

This award in the Inorganic, Bioinorganic and Organometallic Chemistry program supports research by Professor Richard H. Holm at Harvard University that centers on transformations catalyzed by the molybdenum and tungsten oxotransferases and hydroxylases. Many of these reactions are pure oxygen atom (oxo) transfer processes, in which an oxygen atom is inserted or removed (oxotransferases) while others utilize metalcoordinated hydroxide in the catalytic reaction (hydroxylases). The tungsten-containing enzymes are usually found in hyperthermophilic bacteria and archaea. In practically all cases, the ultimate source or sink of oxygen atoms is water. The catalytic centers contain mononuclear molybdenum or tungsten atoms bound to one or two pyranopterindithiolene ligands. The experimental approach involves the synthesis of low molecular weight analogues of the catalytic sites of enzymes and their utilization in reactivity investigations. The research builds upon synthetic and reactivity results with analogues of the catalytic sites of enzymes that contain two pyranopterindithiolene ligands and reduce organic S-oxides and N-oxides by atom transfer. The natural ligand is represented by a synthetic dithiolene, which functions as an ene-1,2-dithiolate when bound to molybdenum or tungsten and closely simulates the electronic environment engendered by the native coordination. A new and possibly general method of synthesis of dithiolene complexes is proposed in order to examine analogue reactions of the enzymes selenate reductase, arsenite oxidase, formate dehydrogenase, acetylene hydratase, aldehyde oxidase, and carbon monoxide dehydrogenase. Other systems include the transhydroxylases and ethylbenzene dehydrogenase. Functional analogue systems that transform substrates as do enzymes (but not necessarily in the same reaction rate domain) with metal sites credibly similar to those of the enzymes and providing close approaches to enzyme-site geometric and electronic structures, are the focus of this research. Molybdenum and tungsten enzymes are implicated in global cycles thet process carbon, nitrogen, sulfur, arsenic, and selenium. Certain enzymes such as the sulfite and xanthine oxidases occur in humans; their malfunction leads to significant health risks. For example, the absence of sulfite oxidase can lead to mental retardation. Reduced ability to biosynthesize the pyranopterindithiolene ligand will lead to deficiencies in all molybdoenzymes with accompanying diseases including neurological syndromes. The broader potential impact of the proposed research derives from a better understanding of the structure, function, and mechanism of biological molybdenum/tungsten centers at all levels, and an integration of that information into improved interpretation of geochemical and environmental cycles of the these elements and those contained in enzymatic substrates.